Influence of Solvent Selection on the Crystallizability and Polymorphic Selectivity Associated with the Formation of the "Disappeared" Form I Polymorph of Ritonavir.

The comparative crystallizability and polymorphic selectivity of ritonavir, a novel protease inhibitor for the treatment of acquired immune-deficiency syndrome, as a function of solvent selection are examined through an integrated and self-consistent experimental and computational molecular modeling study. Recrystallization at high supersaturation by rapid cooling at 283.15 K is found to produce the metastable "disappeared" polymorphic form I from acetone, ethyl acetate, acetonitrile, and toluene solutions in contrast to ethanol which produces the stable form II. Concomitant crystallization of the other known solid forms is not found under these conditions. Isothermal crystallization studies using turbidometric detection based upon classical nucleation theory reveal that, for an equal induction time, the required driving force needed to initiate solution nucleation decreases with solubility in the order of ethanol, acetone, acetonitrile, ethyl acetate, and toluene consistent with the expected desolvation behavior predicted from the calculated solute solvation free energies. Molecular dynamics simulations of the molecular and intermolecular chemistry reveal the presence of conformational interplay between intramolecular and intermolecular interactions within the solution phase. These encompass the solvent-dependent formation of intramolecular O-H...O hydrogen bonding between the hydroxyl and carbamate groups coupled with differing conformations of the hydroxyl's shielding phenyl groups. These conformational preferences and their relative interaction propensities, as a function of solvent selection, may play a rate-limiting role in the crystallization behavior by not only inhibiting to different degrees the nucleation process but also restricting the assembly of the optimal intermolecular hydrogen bonding network needed for the formation of the stable form II polymorph.

Insoluble Salt of Memantine with a Unique Fluorescence Phenomenon.

Alzheimer's disease is a chronic disease, and the long-term treatment of chronic diseases has always been a concern. Memantine (Mem) is approved by the US Food and Drug Administration for the treatment of moderate to severe Alzheimer's disease. In this study, reactions of memantine (Mem) with pamoic acid (Pam) were carried out to form insoluble salts (Mem-Pam). Four polymorphic forms (Forms I-IV) of Mem-Pam were successfully obtained through polymorphic screening, which were systematically characterized by X-ray powder diffraction (PXRD), thermal analysis (TGA and DSC), single-crystal X-ray diffraction (SXRD), and solid-state fluorescence. Compared with the hydrochloride form, the dissolution and release rates of these four forms are lower. The presence of pamoic acid reduces the release rate of memantine and makes it possible to achieve a sustained release of the drug. Interestingly, because of the presence of memantine, each polymorphic solid crystal of Mem-Pam has unique fluorescence emission. Therefore, memantine and pamoic acid have a synergistic effect on the fluorescence performance and can be expected to be used for real-time monitoring in continuous and controlled release drug delivery systems. In addition, the polymorphic solid crystals also exhibit reversible mechanochromic luminescence under the fumigation of acetonitrile vapor, which has a guiding role in the fluorescence design and synthesis of Pam substances and is expected to be used for information security, visual inspection of organic substances, etc.

Molecular, Solid-State and Surface Structures of the Conformational Polymorphic Forms of Ritonavir in Relation to their Physicochemical Properties.

PURPOSE: Application of multi-scale modelling workflows to characterise polymorphism in ritonavir with regard to its stability, bioavailability and processing. METHODS: Molecular conformation, polarizability and stability are examined using quantum mechanics (QM). Intermolecular synthons, hydrogen bonding, crystal morphology and surface chemistry are modelled using empirical force fields. RESULTS: The form I conformation is more stable and polarized with more efficient intermolecular packing, lower void space and higher density, however its shielded hydroxyl is only a hydrogen bond donor. In contrast, the hydroxyl in the more open but less stable and polarized form II conformation is both a donor and acceptor resulting in stronger hydrogen bonding and a more stable crystal structure but one that is less dense. Both forms have strong 1D networks of hydrogen bonds and the differences in packing energies are partially offset in form II by its conformational deformation energy difference with respect to form I. The lattice energies converge at shorter distances for form I, consistent with its preferential crystallization at high supersaturation. Both forms exhibit a needle/lath-like crystal habit with slower growing hydrophobic side and faster growing hydrophilic capping habit faces with aspect ratios increasing from polar-protic, polar-aprotic and non-polar solvents, respectively. Surface energies are higher for form II than form I and increase with solvent polarity. The higher deformation, lattice and surface energies of form II are consistent with its lower solubility and hence bioavailability. CONCLUSION: Inter-relationship between molecular, solid-state and surface structures of the polymorphic forms of ritonavir are quantified in relation to their physical-chemical properties.

Cocrystal Solubility Advantage Diagrams as a Means to Control Dissolution, Supersaturation, and Precipitation.

Cocrystals are often more soluble than needed and pose unnecessary risks for precipitation of less soluble forms of the drug during processing and dissolution. Such conversions lead to erratic cocrystal behavior and nullify the cocrystal solubility advantage over parent drug (SA = Scocrystal/Sdrug). This work demonstrates a quantitative method for additive selection to control cocrystal disproportionation based on cocrystal solubility advantage (SA) diagrams. The tunability of cocrystal SA is dependent on the selective drug-solubilizing power of surfactants (SPdrug = (ST/Saq)drug). This cocrystal property is used to generate SA-SP diagrams that facilitate surfactant selection and provide a framework for evaluating how SA influences drug concentration-time profiles associated with cocrystal dissolution, drug supersaturation, and precipitation (DSP). Experimental results with indomethacin-saccharin cocrystal and surfactants (sodium lauryl sulfate, Brij, and Myrj) demonstrate the log-linear relationship characteristic of SA-SP diagrams and the dependence of σmax and dissolution area under the curve (AUC) on SA with characteristic maxima at a threshold supersaturation where drug nucleation occurs. This approach is expected to streamline cocrystal formulation as it facilitates additive selection by considering the interplay between thermodynamic (SA) and kinetic (DSP) processes.

Formation and Transformation Behavior of Sodium Dehydroacetate Hydrates.

The effect of various controlling factors on the polymorphic outcome of sodium dehydroacetate crystallization was investigated in this study. Cooling crystallization experiments of sodium dehydroacetate in water were conducted at different concentrations. The results revealed that the rate of supersaturation generation played a key role in the formation of the hydrates. At a high supersaturation generation rate, a new sodium dehydroacetate dihydrate needle form was obtained; on the contrary, a sodium dehydroacetate plate monohydrate was formed at a low supersaturation generation rate. Furthermore, the characterization and transformation behavior of these two hydrated forms were investigated with the combined use of microscopy, powder X-ray diffraction (PXRD), Raman spectroscopy, Fourier transform infrared (FTIR), thermal gravimetric analysis (TGA), scanning electron microscopy (SEM) and dynamic vapor sorption (DVS). It was found that the new needle crystals were dihydrated and hollow, and they eventually transformed into sodium dehydroacetate monohydrate. In addition, the mechanism of formation of sodium dehydroacetate hydrates was discussed, and a process growth model of hollow crystals in cooling crystallization was proposed.

Biocompatible Nano-Cocrystal Engineering for Targeted Herbicide Delivery: Enhancing Efficacy through Stimuli-Responsive Release and Reduced Environmental Losses.

In addressing the critical challenges posed by the misuse and inefficiency of traditional pesticides, we introduce a Nano-Cocrystal material composed of the herbicide clopyralid and coformer phenazine. Developed through synergistic supramolecular self-assembly and mechanochemical nanotechnology, this Nano-Cocrystal significantly enhances pesticide performance. It exhibits a marked improvement in stability, with reductions in hygroscopicity and volatility by approximately 38%. Moreover, it intelligently modulates release according to environmental factors, such as temperature, pH, and soil inorganic salts, demonstrating decreased solubility by up to four times and improved wettability and adhesion on leaf surfaces. Importantly, the herbicidal activity surpasses that of pure clopyralid, increasing suppression rates of Medicago sativa L. and Oxalis corniculata L. by up to 27% at the highest dosage. This Nano-Cocrystal also shows enhanced crop safety and reduced genotoxicity compared to conventional formulations. Offering a blend of simplicity, cost-effectiveness, and robust stability, our findings contribute a sustainable solution to agricultural practices, favoring the safety of nontarget organisms.

Pursuing Green and Efficient Agriculture from Molecular Assembly: A Review of Solid-State Forms on Agrochemicals.

Achieving rapid global agricultural development while maintaining ecological harmony is a major challenge of the new millennium. Meeting this challenge requires the development of efficient and environmentally friendly agrochemicals, including pesticides and fertilizers. Molecular assembly, as a promising strategy, has garnered significant attention in recent years for the development of advanced solid-state forms of agrochemicals. In this review, we present the potential and recent advancements of solid-state forms, such as polymorphs, cocrystals/salts, solvates, inclusion compounds, and the amorphous state, for the production of high-efficiency and low-polluting agrochemical products. We provide an overview of the concepts and preparation methods of these solid-state forms, followed by an exploration of their applications in sustainable agriculture. Specifically, we highlight their value in enhancing pesticide solubility, enabling controlled release of chemical fertilizers, and reducing off-target risks. Lastly, we discuss the challenges and prospects associated with the utilization of solid-state forms for the advancement of environmentally friendly and efficient agriculture.

Ultrasound-assisted continuous crystallization of metastable polymorphic pharmaceutical in a slug-flow tubular crystallizer.

Metastable polymorphic pharmaceuticals have garnered significant attention in recent years due to their enhanced physicochemical properties, including solubility, bioavailability, and intellectual property considerations. However, the manufacturing of metastable form pharmaceuticals remains a formidable challenge. The stable preparation of metastable carvedilol (CVD) form Ⅱ crystals during CVD production is elusive, leading to substantial inconsistencies in product quality and regulatory compliance. In this study, we successfully prepared metastable CVD Form Ⅱ crystals using a continuous tubular crystallizer. Our findings demonstrate that the tubular crystallizer exhibits high efficiency and robustness for generating metastable crystal Form Ⅱ. We optimized the crystallization process by incorporating air bubble segments and employing ultrasonic irradiation strategies to overcome blockages and wall sticking issues encountered during operation. Ultimately, we developed an ultrasound-assisted continuous slug-flow tubular crystallization method and evaluated its performance. The results indicate that the CVD crystals produced through this process are resilient, sustainable, and uninterrupted products with promising potential for producing metastable polymorphic pharmaceuticals while effectively addressing encrustation problems associated with continuous tubular crystallization.

Effects of various parameters on solution-mediated phase transformation of calcium d-gluconate: an approach to obtain pure metastable monohydrate.

The high risk of solution-mediated phase transformation (SMPT) from the metastable monohydrate to stable Form I makes it difficult to produce pure metastable monohydrate of calcium d-gluconate. In this work, we explored the effect of various operating parameters on the SMPT of calcium d-gluconate in water and proposed an effective approach to obtain the desired monohydrate. First, the two forms of calcium d-gluconate were characterized and compared using powder X-ray diffraction (PXRD), thermal analysis, and Raman spectroscopy. The lower solubility of Form I in water illustrates its higher thermodynamic stability than monohydrate when the temperature is higher than 292 K. Afterward, the SMPT of calcium d-gluconate from monohydrate to Form I was investigated in water using in situ Raman spectroscopy combined with scanning electron microscopy and PXRD. Results showed that the nucleation and growth of Form I was the rate-limiting step in the SMPT from monohydrate to Form I. The phase transformation from monohydrate to Form I was delayed to produce pure monohydrate by decreasing temperature and agitation rate, reducing the amount of solid loading, and increasing the particle size of solid loading. Furthermore, the transformation kinetics were studied by the JMA model to explore how temperature influences the SMPT process. This study enriches the study of the calcium d-gluconate SMPT mechanism, and also provides guidance for obtaining high-quality injection-grade calcium gluconate monohydrate.

Designing sequence-defined peptoids for fibrillar self-assembly and silicification.

In the biological environment, mineral crystals exquisitely controlled by biomacromolecules often show intricate hierarchical structures and superior mechanical properties. Among these biominerals, spicules, hybrid silica/protein superstructures serving as skeletal elements in demosponges, represent an excellent example for motivating the synthesis of silica materials. Herein, by designing sequence-defined peptoids containing side chains with a strong binding to silica, we demonstrated that self-assembly of these peptoids into fiber structures enables the mimicking of both biocatalytic and templating functions of silicatein filaments for the formation of silica fibers at near-neutral pH and ambient temperature. We further showed that the presence of amino groups is significant for the nucleation of silica on self-assembled peptoid nanofibers. Molecular dynamics simulation further confirmed that having silica-binding of amino side chains is critical for self-assembled peptoid fibers in triggering silica formation. We demonstrated that tuning inter-peptoid interactions by varying carboxyl and amino side chains significantly influences the assembly kinetics and final morphologies of peptoid assemblies as scaffolds for directing silica mineralization to form silica spheres, fibers, and sheets. The formation of silica shell on peptoid fibers increased the mechanical property of peptoid hydrogel materials by nearly 1000-fold, highlighting the great potential of using silicification to enhance the mechanical property of hydrogel materials for applications including tissue engineering. Since peptoids are highly robust and programmable, we expect that self-assembly of peptoids containing solid-binding side chains into hierarchical materials opens new opportunities in the design and synthesis of highly tunable scaffolds that direct the formation of composite nanomaterials.

Insights into the Biomimetic Synthesis of 2D ZnO Nanomaterials through Peptoid Engineering.

Achieving predictable biomimetic crystallization using sequence-defined synthetic molecules in mild conditions represents a long-standing challenge in materials synthesis. Herein we report a peptoid-based approach for biomimetic control over the formation of nanostructured ZnO materials in ambient aqueous conditions. A series of two-dimensional (2D) ZnO nanomaterials have been successfully obtained using amphiphilic peptoids with different numbers, ratios, and patterns of various hydrophilic and hydrophobic side chains. By investigating the relationship between peptoid hydrophobicity and the thickness of the resultant ZnO nanomaterials, we found the critical role of peptoid hydrophobicity in the peptoid-controlled ZnO formation. Our results suggest that tuning the hydrophobicity of peptoids can be used to moderate peptoid-ZnO surface interactions, thus controlling the formation of ultrathin (<2.5 nm) 2D ZnO nanomaterials. The peptoid-controlled formation of ZnO nanomaterials was further investigated using ultrasmall-angle X-ray scattering (USAXS). Our work suggests a new approach to synthesizing 2D metal oxide nanomaterials using sequence-defined synthetic molecules.

Solubility of disodium 5'-guanylate heptahydrate in aqueous methanol mixtures.

The solubility of disodium 5'-guanylate heptahydrate (5'-GMPNa2) in binary aqueous methanol solvent mixtures with the temperature ranging from 278.15 to 323.15K was measured by a dynamic method with a laser monitoring observation technique. The solubility data were correlated with the Combined Nearly Ideal Binary Solvent/Redlich-Kister (CNIBS/R-K) model and the modified Jouyban-Acree model, respectively. For the ten groups of data studied, the CNIBS/R-K model was found to provide a more accurate mathematical representation of the experimental data, while the modified Jouyban-Acree model containing provisions for correlating both the solvent composition and temperature.

Bioinspired double self-adhesion coating based on dopamine, coating resin and phosphorylcholine for surface lubrication and antifouling functionalization.

Implanted medical devices that have poor friction property or biofilm formation can limit their service life and cause discomfort in patients. Recently, some zwitterionic coatings have been studied to modify the biomaterials surface for lubricating function, but the grafting methods of coatings are complicated and also seldom take the bacterial antiadhesion property into account at the same time. In our studies, motivated by the properties of nature mussels and human articular, we firstly successfully synthesized double adhesion protection of self-adhesive ternary polymer coating and achieved the excellent lubrication and antifouling functionalization of the medical devices surface. In details, the X-ray photoelectron spectroscopy, scanning electron microscope and the water contact angles could characterize the successful modification on the surface of titanium substrate. Additionally, the tribological tests carried out by atomic force microscope verified the ternary polymer could enhance the lubrication property owing to the hydration lubrication mechanism. Meanwhile, it also possessed the bacterial antiadhesion property for the initial 24 h attributed to the hydration repulsive force. We believe that, as a simple and universal preparation method, the ternary polymer could make a great significance for improving the surface function of biomaterials and alleviating patients' discomfort.

Triglycine (GGG) Adopts a Polyproline II (pPII) Conformation in Its Hydrated Crystal Form: Revealing the Role of Water in Peptide Crystallization.

Polyproline II (pPII) is a left-handed 31-helix conformation, which has been observed to be the most abundant secondary structure in unfolded peptides and proteins compared to α-helix and ß-sheet. Although pPII has been reported as the most stable conformation for several unfolded short chain peptides in aqueous solution, it is rarely observed in their solid state. Here, we show for the first time a glycine homopeptide (gly-gly-gly) adopting the pPII conformation in its crystalline dihydrate structure. The single crystal X-ray structure with molecular dynamic simulation suggests that a network of water and the charged carboxylate group is critical in stabilizing the pPII conformation in solid state, offering an insight into the structures of unfolded regions of proteins and the role of water in peptide crystallization.

Imidazolium 3-nitro-benzoate.

In the title compound, C(3)H(5)N(2) (+)·C(7)H(4)NO(4) (-), the benzene ring forms a dihedral angle of 40.60 (5)° with the imidizolium ring. The nitro-benzoate anion is approximately planar: the benzene ring makes dihedral angles of 3.8 (3) and 3.2 (1)° with the nitro and carboxyl-ate groups, respectively. In the crystal structure, the cations and anions are linked by inter-molecular N-H⋯O hydrogen bonds, forming a zigzag chain along the b axis.

A Novel Route to Manufacture 2D Layer MoS2 and g-C3N4 by Atmospheric Plasma with Enhanced Visible-Light-Driven Photocatalysis.

An atmospheric plasma treatment strategy was developed to prepare two-dimensional (2D) molybdenum disulfide (MoS2) and graphitic carbon nitride (g-C3N4) nanosheets from (NH4)2MoS4 and bulk g-C3N4, respectively. The moderate temperature of plasma is beneficial for exfoliating bulk materials to thinner nanosheets. The thicknesses of as-prepared MoS2 and g-C3N4 nanosheets are 2-3 nm and 1.2 nm, respectively. They exhibited excellent photocatalytic activity on account of the nanosheet structure, larger surface area, more flexible photophysical properties, and longer charge carrier average lifetime. Under visible light irradiation, the hydrogen production rates of MoS2 and g-C3N4 by plasma were 3.3 and 1.5 times higher than the corresponding bulk materials, respectively. And g-C3N4 by plasma exhibited 2.5 and 1.3 times degradation rates on bulk that for methyl orange and rhodamine B, respectively. The mechanism of plasma preparation was proposed on account of microstructure characterization and online mass spectroscopy, which indicated that gas etching, gas expansion, and the repulsive force of electron play the key roles in the plasma exfoliation. Plasma as an environmentally benign approach provides a general platform for fabricating ultrathin nanosheet materials with prospective applications as photocatalysts for pollutant degradation and water splitting.

Confined Crystallization of Pigment Red 146 in Emulsion Droplets and Its Mechanism.

In this work, the effect of confined space on crystallization processes of pigments was investigated by using C.I. Pigment Red 146 (PR 146) as a model compound. The colloidal system (i.e., emulsion droplets) was used as a nanoreactor to prepare nanoscale PR 146 for the inkjet printer. The effects of the space confinement were investigated by comparing the products of PR 146 prepared from bulk solution, macroemulsion, and miniemulsion. The results showed that PR 146 crystallized in mini-emulsion had the narrowest particle size distribution and the average particle size can be as small as 172.5 nm, one order of magnitude smaller than the one obtained from the bulk solution. X-ray diffraction (XRD) data revealed that PR 146 crystallized in all three solutions where the crystalline state and had similar crystallite sizes. The process mechanism of crystallization confined in the miniemulsion droplets was proposed and explained. The function mechanism of the co-stabilizer during the crystallization of PR 146 in emulsion was also explained. It was found that sodium chloride could counteract the pressure difference as an osmotic pressure agent and prevent the migrating of water from small droplets into big droplets. The influences of dosages of emulsifiers and co-stabilizers on droplet size and the size of the obtained PR 146 particles were evaluated and the optimal conditions were determined. Furthermore, the disparity of PR 146 products prepared by different methods was investigated by UV⁻Vis spectra. The aqueous dispersion of PR 146 crystallized in miniemulsion had the highest absorbance and darkest color.

Consistency and variability of cocrystals containing positional isomers: the self-assembly evolution mechanism of supramolecular synthons of cresol-piperazine.

The disposition of functional groups can induce variations in the nature and type of interactions and hence affect the molecular recognition and self-assembly mechanism in cocrystals. To better understand the formation of cocrystals on a molecular level, the effects of disposition of functional groups on the formation of cocrystals were systematically and comprehensively investigated using cresol isomers (o-, m-, p-cresol) as model compounds. Consistency and variability in these cocrystals containing positional isomers were found and analyzed. The structures, molecular recognition and self-assembly mechanism of supramolecular synthons in solution and in their corresponding cocrystals were verified by a combined experimental and theoretical calculation approach. It was found that the heterosynthons (heterotrimer or heterodimer) combined with O-H⋯N hydrogen bonding played a significant role. Hirshfeld surface analysis and computed interaction energy values were used to determine the hierarchical ordering of the weak interactions. The quantitative analyses of charge transfers and molecular electrostatic potential were also applied to reveal and verify the reasons for consistency and variability. Finally, the molecular recognition, self-assembly and evolution process of the supramolecular synthons in solution were investigated. The results confirm that the supramolecular synthon structures formed initially in solution would be carried over to the final cocrystals, and the supramolecular synthon structures are the precursors of cocrystals and the information memory of the cocrystallization process, which is evidence for classical nucleation theory.

Bis(1-methyl-1-phenyl-ethyl) peroxide.

In the crystal structure, the title compound (also called dicumyl peroxide), C(18)H(22)O(2), lies on a center of symmetry. The COOC plane including the di-oxy group makes a dihedral angle of 79.10 (5)° with the phenyl ring. An inter-molecular C-H⋯π inter-action is observed between the phenyl groups.

Insights into the mechanism of concomitant nucleation of form II and ethanol solvate of spironolactone in cooling crystallization.

The concomitant crystallization of spironolactone form II and its ethanol solvate was investigated in ethanol by means of process analytical techniques, such as particle vision and measurement (PVM), focused beam reflectance measurement (FBRM) and Raman spectroscopy. The concomitant crystals were characterized by optical microscopy, powder X-ray diffraction, differential scanning calorimetry and thermogravimetric analysis. Analysis results of primary nucleation kinetics based on the experimental data of the induction time show that the ethanol solvate is the kinetically favored form with a lower interfacial energy, a higher nucleation rate and a smaller radius of the critical nucleus, compared with form II. At a high supersaturation, the crystallization process is dominated by kinetic factors and only the ethanol solvate is obtained. Whereas, at a low supersaturation, only form II crystallizes out owing to its thermodynamic priority. At a moderate supersaturation, concomitant crystals are found as a result of their nearly equal nucleation rates. In summary, the real cause for concomitant crystallization of form II and ethanol solvate of spironolactone is their simultaneous nucleation.